Neurokinin 1 receptor blockade is associated with increased survival of patients with C. difficile infection

Clostridioides difficile, a significant cause of healthcare-associated infections, leads to a toxin-mediated disease via the secretion of Toxin A and Toxin B. These toxins cause neurogenic inflammation, which contributes to intestinal inflammation in animal models. Substance P (SP), a vasoactive neuropeptide, is a key player in C. difficile toxin-induced inflammation. SP interacts with multiple receptors, including the high-affinity neurokinin-1 receptor (NK1-R) and lower-affinity receptors.

In vivo mouse infection models confirmed that SP's effects in hypervirulent C. difficile infections are largely mediated by NK1-R. Genetic mice lacking mast cells, which respond to SP in certain neurogenic inflammations, showed similar inflammation levels, indicating that mast cells are not crucial for C. difficile-induced inflammation.

The researchers then investigated the role of NK1-R antagonists in a retrospective study of a large clinical cohort. After propensity matching, they found that NK1-R antagonists were associated with a significant survival benefit. Patients treated with these antagonists also displayed reduced vascular inflammation, as evidenced by increased serum albumin.

These findings suggest that blocking SP activity through NK1-R antagonism with small molecule inhibitors could be a valuable approach for adjunctive treatment during C. difficile infection.